New Computational Model for miRNA-mediated Repression Reveals Novel Regulatory Roles of miRNA Bindings Inside the Coding Region

MicroRNAs (miRNAs) are short (~24nt), non-coding RNAs, which downregulate gene expression in many species and physiological processes. They bind to target sites in the mRNA and recruit the RNA-Induced Silencing Complex (RISC), facilitating both translation inhibition and mRNA degradation. Effective miRNA target sites mostly reside in the 3`UTR, but functional sites were also shown to exist in the coding sequence. However, many details regarding the mechanism which governs miRNA-mediated repression continue to elude researchers. Here we elucidate the interplay between the coding sequence and the 3`UTR, by developing a computational model using elastic net regularization to predict miRNA-mediated repression. We found that miRNA binding sites at the end of the coding sequence contribute to the repression, and that weak binding sites are linked to effective de-repression as a result of competing with stronger binding sites. Furthermore, we propose a recycling model for miRNAs dissociated from the Open reading frame (ORF) by traversing ribosomes, explaining the observed link between increased ribosome density/traversal speed and increased repression. This model is supported by analysis of Ribo-Seq data and improves the predictive power of miRNA-mediated repression by 49%. Our results uncover a novel layer of interaction between the coding sequence and the 3`UTR (untranslated region) and suggest the ORF has a larger role than previously thought in the mechanism of miRNA-mediated repression.